The pharmacological action of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles rests on their ability to reduce effectively the cytozolic concentration of calcium ions, when intracellular concentration of calcium ions has become excessive as a result of various pathological processes. Besides, these compounds are effective antagonists of 5-HT6 serotonin receptors, playing an important role in treatment diseases associated with central nervous system (CNS), such as Alzheimer's disease, Huntington's disease, schizophrenia or other neurodegenerative diseases, and obesity.
Maintenance of low concentration of calcium ions is extremely important for normal cell functioning, because the prolonged enhancement of Ca+2 percentages in cytozole leads to apoptosis. Such mechanism of apoptosis is a characteristic feature of all neurodegenerative diseases, that is why the searching for pharmacological remedies preventing excessive penetration of Ca+2 ions into neurons is one of the most important trend in neuroprotector development [Kiewert C., Hartmann J., Stoll J., Thekkumkara T. J., Van der Schyf C. J., Klein J. NGP1-01 is a Brain-permeable Dual Blocker of Neuronal Voltage- and Ligand-operated Calcium Channels. Neurochem. Res. 2006 May 3]. Cytozolic Ca+2 concentration in eucariotic cells is regulated by transmembrane transport and by cytoplasm calcium binding [Sayer R. J. Intracellular Ca2+ handling. Adv Exp Med Biol. 2002; 513:183-96].
Obviously, the various proteins supporting calcium homeostasis in cytoplasm play an extraordinary role in pathogenesis of such neuralgic disorders as hypoxia-ischemia, hypoglycemia, convulsive conditions, cerebral traumas and also chronic neurodegenerative diseases (including Alzheimer's disease, Huntington's chorea, lathyrism, lateral amyotrophic sclerosis). [J. W. McDonald, M. V. Johnston—Brain Res. Rev., 1990; 15:41-70; Stys P. K. General mechanisms of axonal damage and its prevention. J Neurol Sci. 2005; 233(1-2):3-b]. The possibility of pool regulation of intracellular Ca+2 concentration determines the great pharmacological role of selective blockers/activators of various potential dependent calcium channels (for example, T-, L-, N—, P—, Q- and R— channels) and specific antagonist/modulator of ligand-gated channels (for example, NMDA-, AMPA-, nAChR-, P2X-receptors) [Barry P. H., Lynch J. W. Ligand-gated channels. IEEE Trans Nanobioscience. 2005; 4(1):70-80]. At present a great number of such calcium transport effectors are offered as highly effective medicaments. For example, calcium antagonists—is a group of drugs the common feature of which is the ability to reversible blocking of calcium flow through potential-dependent calcium channels. Judging by their chemical structure these drugs could be divided into two large subgroups dihydropyridines (Nifedipine, Amlodipine, Felodipine and others), in the properties of which the effect of peripheric vasodilatation is predominated, and nondihydropyridines (Verapamil and Diltiazem), the main properties of which is negative chrono- and inotropic action and the ability to reduce atrioventricular conductibility as well [Sica D. A. Pharmacotherapy review: calcium channel blockers. [J Clin Hypertens (Greenwich). 2006; 8(1):53-6]. An example of a drug blocking an excessive penetration of calcium ions into neurons through ligand-gated channels (NMDA) is Memantine, widely used at present in the treatment of Alzheimer's disease [Rogawski M. A., Wenk G. L. The neuropharmacological basis for the use of Memantine in the treatment of Alzheimer's disease. [CNS Drug Rev. 2003; 9(3):275-308]. Nearly all mentioned drugs prevent the excessive penetration of calcium ions into cells, however, calcium homeostasis modulators capable to effective reducing of calcium cytosolic concentration which became excessive as a result of some pathologic processes have not been known yet
Use of effective and selective antagonists of 5-HT6 serotonin receptors for treatment diseases associated with CNS, in particular, schizophrenia, Alzheimer's disease and other neurodegenerative diseases is a perspective direction for the development of novel drugs [Holenz J., Pauwels P. J., Diaz J. L., Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299]. At mammals these receptors are found exclusively in the central nervous system (CNS), mainly, in the regions of brain responsible for training and memory [Ge'rard C., Martres M.-P., Lefe'vre K., Miquel M.-C., Verge' D., Lanfurney L., Doucet E., Hamon M., El Mestikawy S. Immuno-localisation of serotonin 5-HT6 receptor-like material in the rat central nervous system. [Brain Research. 1997; 746:207-219]. Moreover, it was shown [Dawson L. A., Nguyen H. Q., Li P. The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. [Neuropsychopharmacology. 2001; 25:662-668], that 5-HT6 receptors are modulators of several neuromediator systems, including cholinergic, noradrenergic, glutamatergic and dopaminergic. Bearing in mind the fundamental role of these systems in normal cognitive processes and also their dysfunction at neurodegeneration, it becomes obvious an exclusive role of 5-NT6 receptors in the functioning of normal or “pathological” memory. In many current publication it was shown, that blocking of 5-HT6 receptors leads to considerable enhancement of memory consolidation in various animal models of training—memorizing—reproduction [Foley A. G., Murphy K. J., Hirst W. D., Gallagher H. C., Hagan J. J., Upton N., Walsh F. S., Regan C. M. The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology. 2004; 29:93-100. Riemer C., Borroni E., Levet-Trafit B., Martin J. R., Poli S., Porter R. H., Bos M. Influence of the 5-HT6 receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT6 receptor antagonist. J. Med. Chem. 2003; 46:1273-1276. King M. V., Woolley M. L., Topham I. A., Sleight A. J., Marsden C. A., Fone K. C. 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation an effect sensitive to NMDA receptor antagonism. Neuropharmacology 2004; 47:195-204]. It was also shown significant improvement of cognitive functions in aged rats in a model of Morris water Maze under the action of 5-HT6 receptor antagonists [Foley A. G., Murphy K. J., Hirst W. D., Gallagher H. C., Hagan J. J., Upton N., Walsh F. S., Regan C. M. The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology. 2004; 29:93-100]. Recently, not merely the more fundamental understanding of 5-HT6 receptors role in cognitive processes was achieved, but also more unambiguous conception concerning pharmacophor possibilities of their antagonists [Holenz J., Pauwels P. J., Diaz J. L., Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents. [Drug Disc. Today. 2006; 11:283-299]. It resulted in creation of high-affinity selective ligandes (“molecular tools”), and then clinical candidates. Now the whole number of 5-HT6 receptor antagonists are at various stages of clinical tests as drug candidates for treatment Alzheimer's disease, Huntington's disease, schizophrenia (antipsychotics) and other neurodegenerative and cognitive diseases (Table 1) [http://integrity.prous.com].
TABLE 15-HT6 receptor antagonists as drug candidates.Clinical phaseDrugof testingSponsorTherapeutic groupDimebon ™Phase IIIMedivation (USA)Treatment ofAlzheimer's diseaseSGS-518Phase IILilly, SaegisTreatment ofcognitive diseasesSB-742457Phase IIGlaxoSmithKlineTreatment ofAlzheimer's disease;AntipsychoticDimebon*Phase I/IIaMedivation (USA)Treatment ofHuntington'sdiseaseDimebon*Phase II(Russia)AntipsychoticPRX-07034Phase IEpix Pharm.Treatment ofoverweight;Antipsychotic;Treatment ofcognitive diseasesSB-737050APhase IIGlaxoSmithKlineAntipsychoticBVT-74316Phase IBiovitrumTreatment ofoverweight;SAM-315Phase IWyeth Pharm.Treatment ofAlzheimer's diseaseSYN-114Phase IRoche, SynosisTreatment ofTher.cognitive diseasesBGC-20-761PreclinicalBTG (London)Antipsychotic;phaseTreatment ofcognitive diseasesFMPOPreclinicalLillyAntipsychoticphaseDimebon ™Preclinical(Russia)Treatment of Insultphase*in the process of this investigation the authors discovered for the first time that Dimebon is 5-HT6 receptor antagonist and simultaneously regulates homeostasis of calcium ions in cells.
Another attractive property of 5-HT6 receptor antagonists is their ability to suppress appetite that can lead to creation on their bases principally novel remedies for treatment of overweight and obesity [Vicker S. P., Dourish C. T. Serotonin receptor ligands and the treatment of obesity. Curr. Opin. Investig. Drugs. 2004; 5:377-388]. This effect was confirmed in many investigations [Holenz J., Pauwels P. J., Diaz J. L., Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299. Davies S. L. Drug discovery targets: 5-HT6 receptor. Drug Future. 2005; 30:479-495], mechanism of its functioning is based upon suppression of γ-aminobutyric acid signaling by 5-HT6 receptor antagonists and increasing α-melanocyte-stimulating hormone emission, that, eventually, leads to reduction of food consumption [Woolley M. L. 5-ht6 receptors. Curr. Drug Targets CNS Neurol. Disord. 2004; 3:59-79]. At present two 5-HT6 receptor antagonists are at the first phase of clinical testing as drug candidates for weight-reducing treatment (Table 1) [http://integrity.prous.com].
In this context searching for effective neuroprotectors capable to prevent the neurotoxical action of excessive cytosolic calcium and also searching for effective serotonin 5-HT6 receptor antagonists are seemed to be original and perspective approach to design of novel drug substances for treatment of broad spectrum of neuralgic and neurodegenerative diseases.
There are many publications concerning various biologically active 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles, some of them are represented in Table 2.
TABLE 2Some examples of known 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indolesPharmacologicalNoFormulaactivityReferenceA1Antihistaminic substanceHorlein, Ulrich; Hecht, Gerhard. Med. -Chem., Abhandl. Med.-Chem. Forschungsstatten Farbenfabriken Bayer (1956), 5, 267-80. A2Kost, J. Gen. Chem. USSR (Engl. Transl.), v. 33, 1963, p. 3538. A3Antagonist NMDA- brain receptors. Antihistaminic and neuroprotective substance, Alzheimer's diseaseMashkovsky M.D. Pharmaceuticals. Pub. 13. Kharkov: Torsing, 1998. v.1. p. 280-281. Bull Exp Biol Med. 2000, 129(6) 544-546. U.S. Pat. No. 6187785 (2001) JP 09216882 (1997) RU 2140417 (1999) A4AnalgesicsU.S. Pat. No. 3,502,688 (1972)
For the purpose of searching for novel highly effective neuroprotective drug substances the authors of the invention carried out a broad investigation in the field of substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles; as a result of which new biologically active substances, which are 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles substituted in a certain manner, among them the novel ones, were found.